X-ray mammography has contributed to a reduction in mortality due to breast cancer. It is inherently limited, though, by its inability to directly observe physiological information relevant to the function of cancerous tissue. This ultimately limits the specificity and prognostic ability of x-ray mammography. Diffuse optical tomography (DOT) is a promising imaging modality that provides information on angiogenesis and hemoglobin oxygen saturation - key parameters tied to the presence and evolution of cancer. It suffers, however, from limited spatial resolution and unsatisfactory image quality due to optical coupling variations. These limitations inhibit straightforward interpretation of the optical images obtained and widespread clinical validation of DOT. This obstacle can be overcome by synergistically fusing the optical and x-ray information in a multi-modal imaging configuration - that is, by combining the two modalities, we can overcome their respective limitations and achieve a new multi-modality imaging method with enhanced specificity and prognostic value. Building upon our successful initial collaboration with Philips Healthcare and strong preliminary data, we propose to fundamentally address the current clinical limitations in x-ray mammography by developing a vendor- independent high-performance optical mammography co-imager, or OMCI, with which the optical measurements can be jointly reconstructed using the structural guidance from a separately acquired 2D or 3D digital x-ray mammogram. We believe that this approach has significant advantage from a clinical translation standpoint, as it directly capitalizes on the over 9,000 installed digital mammography systems in the US, and is expected to be compatible with future generations of mammography scanners. The proposed approach will dramatically reduce the time delays, costs, and complex regulatory pathways associated with developing and deploying integrated optical/mammography imaging systems. In the proposed study, we will build a new DOT system architecture for in vivo transmission human imaging and develop innovative prior-guided reconstruction algorithms to utilize high-density optical measurements and significantly enhance the optical image resolution and quality. Supported by a strong clinical team, we will perform a clinical study to explore the sensitivity an specificity of detecting malignant lesions using the proposed system. We will systematically compare the OMCI-assisted mammography diagnosis with stand-alone mammography through a blinded reader study to further confirm the clinical value of the added functional information. This result will prepare us for future multi- center trials and regulatory approval for this new device.